Phenylglycine derivatives pharmaceutical compositions containing them and their use in therapy

ABSTRACT

Compounds of Formula (I) and pharmaceutically acceptable salts thereof: ##STR1## wherein Q is optionally substituted phenyl or naphthyl; 
     X and Y are each H, C 1-6  alkyl, C 2-6  alkenyl or X and Y are together ═O; 
     Z is O or S; 
     R 1  is H, optionally substituted C 1-6  alkyl, optionally substituted phenyl (C 1-4  alkyl), C 2-6  alkenyl, COC 1-6  alkylhalo, COR a , COOR a , CONHR a , COC 1-6  alkylNR a  R b  or CONR a  C 1-6  alkylCONR a  R b  ; 
     R 2  is substituted C 1-6  alkyl, optionally substituted phenyl(C 1-4  alkyl), C 2-6  alkenyl, C 1-6  alkylhalo, COR a , COOR a , CONHR a , COC 1-6  alkylNR a  R b  or CONR a  C 1-6  alkylCONR a  R b  ; 
     or R 1  and R 2  together form a chain (CH 2 ) p  optionally substituted by oxo; 
     R 3  is H [or C 1-6  alkyl]; 
     R 4  is H, C 1-6  alkyl or phenyl; and 
     R 5  is optionally substituted (CH 2 ) q  phenyl; are tachykinin antagonists useful for treating pain.

This application is A 371 of PCT/GB92/01241.

This invention relates to a class of aromatic compounds, which areuseful as tachykinin receptor antagonists.

The tachykinins are a group of naturally-occurring peptides found widelydistributed throughout mammalian tissues, both within the centralnervous system and in the peripheral nervous and circulatory systems.The structures of three known mammalian tachykinins are as follows:

Substance P:

Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH₂

Neurokinin A:

His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH₂

Neurokinin B:

Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH₂

Substance P is believed inter alia to be involved in theneurotransmission of pain sensations [Otsuka et al, "Role of Substance Pas a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia" in 1982Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34(published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Actas a Pain Transmitter?" TIPS (December 1987) 8 506-510], specifically inthe transmission of pain in migraine (B. E. B. Sandberg et al, J. MedChem, (1982) 25 1009) and in arthritis [Levine et al in Science (1984)226 547-549]. These peptides have also been implicated ingastrointestinal (GI) disorders and diseases of the GI tract such asinflammatory bowel disease [Mantyh et al in Neuroscience (1988) 25 (3)817-37 and D. Regoli in "Trends in Cluster Headache" Ed. Sicuteri et alElsevier Scientific Publishers, Amsterdam (1987) page 85)]. It is alsohypothesised that there is a neurogenic mechanism for arthritis in whichsubstance P may play a role [Kidd et al "A Neurogenic Mechanism forSymmetrical Arthritis" in The Lancet, 11 Nov. 1989 and Gronblad et al"Neuropeptides in Synovium of Patients with Rheumatoid Arthritis andOsteoarthritis" in J. Rheumatol. (1988) 15(12) 1807-10]. Therefore,substance P is believed to be involved in the inflammatory response indiseases such as rheumatoid arthritis and osteoarthritis [O'Byrne et alin Arthritis and Rheumatism (1990) 33 1023-8]. Other disease areas wheretachykinin antagonists are believed to be useful are allergic conditions[Hamelet et al Can. J. Pharmacol. Physiol. (1988) 66 1361-7],immunoregulation [Lotz et al Science (1988) 241 1218-21 and Kimball etal, J. Immunol. (1988) 141 (10) 3564-9], vasodilation, bronchospasm,reflex or neuronal control of the viscera [Mantyh et al, PNAS (1988) 853235-9] and, possibly by arresting or slowing β-amyloid-mediatedneurodegenerative changes [Yankner et al, Science (1990) 250, 279-82],in senile dementia of the Alzheimer type, Alzheimer's disease and Down'sSyndrome. Substance P may also play a role in demyelinating diseasessuch as multiple sclerosis and amyotrophic lateral sclerosis [J.Luber-Narod et. al., poster to be presented at C.I.N.P. XVIIIthCongress, 28th Jun.-2nd Jul., 1992, in press], and in disorders ofbladder function such as bladder detrusor hyper-reflexia (Lancet, 16thMay, 1992, 1239).

It has furthermore been suggested that tachykinins have utility in thefollowing disorders: depression, dysthymic disorders, chronicobstructive airways disease, hypersensitivity disorders such as poisonivy, vasospastic diseases such as angina and Reynauld's disease,fibrosing and collagen diseases such as scleroderma and eosinophillicfascioliasis, reflex sympathetic dystrophy such as shoulder/handsyndrome, addiction disorders such as alcoholism, stress related somaticdisorders, neuropathy, neuralgia, disorders related to immuneenhancement or suppression such as systemic lupus erythmatosis (Europeanpatent application no. 0 436 334), ophthalmic disease such asconjuctivitis, vernal conjunctivitis, and the like, and cutaneousdiseases such as contact dermatitis, atropic dermatitis, urticaria, andother eczematoid dermatitis (European patent application no. 0 394 989).

In view of their metabolic instability, peptide derivatives are likelyto be of limited utility as therapeutic agents. It is for this reasonthat non-peptide tachykinin receptor antagonists are sought.

In essence, this invention provides a class of potent non-peptidetachykinin receptor antagonists. By virtue of their non-peptide nature,the compounds of the present invention do not suffer from theshortcomings, in terms of metabolic instability, of known peptide-basedtachykinin receptor antagonists.

European patent application no. 0 194 464 discloses compounds of formula(A): ##STR2## wherein:

R¹ is loweralkyl, arylloweralkyl or optionally substituted phenyl;

R² is inter alia phenyl;

R³ is inter alia H or loweralkyl;

R is inter alia arylloweralkyl; and

n is inter alia 1.

The compounds are said to have anticonvulsant properties.

German patent application no. 28 51 435 discloses compounds of formula(B): ##STR3## wherein:

R is H or CH₃ ; and

R¹ is inter alia a loweralkyl group substituted by an optionallysubstituted phenyl group.

The compounds are said to be useful in heart disease, obesity anddiabetes, through their effect on carbohydrate metabolism.

Canadian patent application no 2,029,338 discloses compounds of formula(C): ##STR4## wherein

Ar is optionally substituted phenyl, 1- or 2-naphthyl or 5- or6-membered heteroaryl;

m is inter alia zero;

Y is H, ##STR5## RCH₂ or ##STR6##

n is inter alia 1;

W is inter alia H or C₁₋₂₀ alkyl; and

Z is inter alia R--CH₂, where R is inter alia optionally substitutedphenyl.

The compounds are said to be ACAT inhibitors useful in lowering bloodcholesterol levels.

Dutch patent application no. 8003601 discloses compounds of formula (D):##STR7## wherein

R¹ is C₁₋₁₀ alkyl;

R² and R³ are H or C₁₋₁₀ alkyl;

R⁴ is inter alia optionally substituted phenyl;

R⁵ is inter alia optionally substituted phenyl;

n is inter alia zero;

m is inter alia 1;

p is inter alia 1; and

q is inter alia zero.

The compounds are said to have anti-spasmolytic, anaesthetic andanalgesic activity.

European patent applicaiton no. 0 384 088 discloses (+)2-N,N-dimethylamino-1-(3,4,5-trimethoxyphenyl)methyloxy)-2-phenylbutaneas an opiate receptor ligand of use in the treatment of gastrointestinaldisorders.

The present invention provides a compound of formula (I), or a salt orprodrug thereof: ##STR8## wherein

Q represents optionally substituted phenyl, optionally substitutedheteroaryl or optionally substituted naphthyl;

X and Y each represent H, C₁₋₆ alkyl, C₂₋₆ alkenyl or X and Y togetherform a group ═O;

Z represents O or S;

R¹ represents H; C₁₋₆ alkyl optionally substituted by hydroxy, cyano,COR^(a), COOR^(a), CONR^(a) R^(b), COC₁₋₄ alkylNR^(a) R^(b), CONR^(a)C₁₋₄ alkylCONR^(a) R^(b) or NR^(a) R^(b), (where R^(a) and R^(b) eachindependently represent H, C₁₋₆ alkyl, phenyl optionally substituted byone or more of C₁₋₆ alkyl, C₁₋₆ alkoxy, halo or trifluoromethyl orphenyl(C₁₋₄ alkyl) optionally substituted in the phenyl ring by one ormore of C₁₋₆ alkyl, C₁₋₆ alkoxy, halo or trifluoromethyl); phenyl(C₁₋₄alkyl), (optionally substituted in the phenyl ring by one or more ofC₁₋₆ alkyl, C₁₋₆ alkoxy, halo or trifluoromethyl); C₂₋₆ alkylene;COR^(a) ; COOR^(a) ; CONHR^(a) ; COC₁₋₆ alkylhalo; COC₁₋₆ alkylNR^(a)R^(b) ; or CONR^(a) C₁₋₆ alkylCONR^(a) R^(b), where R^(a) and R^(b) areas previously defined;

R² represents C₁₋₆ alkyl substituted by hydroxy, cyano, COR^(a),COOR^(a), CONR^(a) R^(b), COC₁₋₄ alkylNR^(a) R^(b), CONR^(a) C₁₋₄alkylCONR^(a) R^(b) or NR^(a) R^(b), (where R^(a) and R^(b) are as abovedefined); phenyl(C₁₋₄ alkyl), (optionally substituted by one or more ofC₁₋₆ alkyl, C₁₋₆ alkoxy, halo and trifluoromethyl in the phenyl ring);C₂₋₆ alkylene; COR^(a) ; COOR^(a) ; CONHR^(a) ; COC₁₋₆ alkylhalo; COC₁₋₆alkylNR^(a) R^(b) ; or CONR^(a) C₁₋₆ alkylCONR^(a) R^(b), where R^(a)and R^(b) are as previously defined;

or R¹ and R² together form a chain (CH₂)_(p) optionally substituted byoxo; where p is 4 or 5 and where one methylene group may optionally bereplaced by an oxygen atom or a group NR^(x), where R^(x) is H or C₁₋₆alkyl;

R³ represents H or C₁₋₆ alkyl;

R⁴ represents H, C₁₋₆ alkyl or phenyl (optionally substituted by one ormore of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, cyano, nitro,trifluoromethyl, trimethylsilyl, SR^(c), SOR^(c), SO₂ R^(c), OR^(c),NR^(c) R^(d), NR^(c) COR^(d), NR^(c) COOR^(d), COOR^(c) or CONR^(c)R^(d), where R^(c) and R^(d) each independently represent H, C₁₋₆ alkyl,phenyl or trifluoromethyl); and

R⁵ represents (CH₂)_(q) phenyl, wherein q is 0, 1, 2 or 3, which mayoptionally be substituted in the phenyl ring by one or more of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, cyano, nitro, trifluoromethyl,trimethylsilyl, SR^(c), SOR^(c), SO₂ R^(c), OR^(c), NR^(c) R^(d), NR^(c)COR^(d), NR^(c) COOR^(d), COOR^(c) or CONR^(c) R^(d), where R^(c) andR^(d) are as above defined; with the exception ofN-(tert-butyoxycarbonyl)-D-4-hydroxyphenylglycine benzyl ester,1-acetamido-2-benzylthio-1-phenylethane,1-((cyanomethyl)amino)-2-benzyloxy-1-phenylethane andα-(acetyl-methylamino)-α-methyl-5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidineaceticacid, phenylmethylester.

The alkyl, alkenyl and alkynyl groups referred to with respect to any ofthe above formulae may represent straight, branched or cyclic groups ora combination thereof. Thus, for example, suitable alkyl groups includemethyl, ethyl, n- or iso-propyl, n-, sec-, iso- or tert-butyl,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and cycloalkyl-alkylgroups such as cyclopropylmethyl; suitable alkenyl groups include vinyland allyl; and suitable alkynyl groups include propargyl.

The term "halo" as used herein includes fluoro, chloro, bromo and iodo,especially chloro and fluoro.

Where Q represents optionally substituted phenyl, heteroaryl ornaphthyl, suitable substituents include C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, SR^(c),SOR^(c), SO₂ R^(c), OR^(c), NR^(c) R^(d), NR^(c) COR^(d), NR^(c)COOR^(d), COOR^(c) or CONR^(c) R^(d), (where R^(c) and R^(d) are asabove defined), such as C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo,cyano, nitro, trifluoromethyl, SCH₃, SOCH₃, SO₂ CH₃, OR^(b), NR^(b)R^(c), NR^(b) COR^(c), NR^(b) COOR^(c), COOR^(b) or CONR^(b) R^(c),where R^(b) and R^(c) are as above defined. One or more substituents maybe present and each may be located at any available ring position.

Suitable values of the group Q include phenyl, indolyl, naphthyl,thiophenyl, furanyl, pyridyl, indazolyl, imidazolyl, tetrazolyl,oxazolyl, benzothiophenyl, benzofuranyl and benzimidazolyl.

Preferably Q is optionally substituted phenyl, indolyl, furanyl,thiophenyl or naphthyl. More preferably Q represents optionallysubstituted phenyl.

Preferably X and Y each represents H.

Preferably Z represents O.

In one subgroup of compounds according to the invention, R¹ representsH; C₁₋₆ alkyl optionally substituted by hydroxy, cyano, COR^(a),COOR^(a), CONR^(a) R^(b), COC₁₋₄ alkylNR^(a) R^(b), CONR^(a) C₁₋₄alkylCONR^(a) R^(b) or NR^(a) R^(b), (where R^(a) and R^(b) each are aspreviously defined); phenyl(C₁₋₄ alkyl) (optionally substituted by oneor more of C₁₋₆ alkyl, C₁₋₆ alkoxy, halo and trifluoromethyl in thephenyl ring); C₂₋₆ alkylene; COR^(a) ; COOR^(a) ; CONHR^(a) ; COC₁₋₄alkylNR^(a) R^(b) ; or CONR^(a) C₁₋₄ alkylCONR^(a) R^(b) (where R^(a)and R^(b) are as previously defined) and R² represents C₁₋₆ alkylsubstituted by hydroxy, cyano, COR^(a), COOR^(a), CONR^(a) R^(b), COC₁₋₄alkylNR^(a) R^(b), CONR^(a) C₁₋₄ alkylCONR^(a) R^(b) or NR^(a) R^(b),(where R^(a) and R^(b) each are as previously defined); phenyl(C₁₋₄alkyl) (optionally substituted by one or more of C₁₋₆ alkyl, C₁₋₆alkoxy, halo and trifluoromethyl in the phenyl ring); C₂₋₆ alkylene;COR^(a) ; COOR^(a) ; CONHR^(a) ; COC₁₋₄ alkylNR^(a) R^(b) ; or CONR^(a)C₁₋₄ alkylCONR^(a) R^(b) (where R^(a) and R^(b) are as previouslydefined), or R¹ and R² together form a chain (CH₂)_(p) optionallysubstituted by oxo where p is 4 or 5 and where one methylene group mayoptionally be replaced by an oxygen atom or a group NR^(x), where R^(x)is H or C₁₋₆ alkyl.

In a further subgroup of compounds according to the invention R¹represents H, C₁₋₆ alkyl, phenyl(C₁₋₄ alkyl), COR¹⁶, COOR¹⁶ or CONHR¹⁶,where R¹⁶ is C₁₋₆ alkyl or phenyl, and R² represents phenyl(C₁₋₄ alkyl),COR¹⁶, COOR¹⁶ or CONHR¹⁶, where R¹⁶ is as previously defined

Suitable values for the group R² include C₁₋₆ alkyl substituted by, forexample, cyano, hydroxy, NH₂, CO₂ C₁₋₆ alkyl, COR^(a), CONR^(a) R^(b),CONR^(a) CH₂ CONR^(a) R^(b), especially CONHCH₂ CONH₂, CON(CH₃)CH₂CONH(CH₃) or CON(CH₃)CH₂ CON(CH₃)₂, COC₁₋₄ alkylNR^(a) R^(b), especiallyCOCH₂ NR^(a) R^(b), such as COCH₂ NH₂, C₁₋₆ alkenyl, especially allyland formyl, and chains such as (CH₂)₄, (CH₂)₅ and (CH₂)₂ O(CH₂)₂.

Suitable values for R¹ include those mentioned above for R², andespecially H and C₁₋₆ alkyl, such as methyl, ethyl, propyl andcyclopropylmethyl.

In a preferred group of compounds according to the invention, R¹represents H or methyl and R² represents C₁₋₂ alkyl substituted by agroup selected from hydroxy, cyano, CHO, CO₂ (C₁₋₆ alkyl), CONR^(a)R^(b) and NR^(a) R^(b). More preferably R¹ represents H and R²represents CH₂ CONH₂.

Suitable values for the group R³ include H and methyl, preferably H.

Preferably R⁴ represents H.

Suitably R⁵ represents (CH₂)_(q) phenyl where q is 0, 1 or 2 and thephenyl group is substituted. Suitable phenyl substituents includemethyl, methoxy, nitro, cyano, halo and trifluoromethyl. Preferably R⁵represents a substituted phenyl group. More preferably R⁵ represents3,5-dimethylphenyl or 3,5-bistrifluoromethylphenyl.

A preferred sub-group of compounds according to the invention isrepresented by formula (Ia) ##STR9## wherein

R¹, R², R³ and Z are as defined for formula (I) above;

R²⁰ and R²¹ each independently represent H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl,SR^(c), SOR^(c), SO₂ R^(c), OR^(c), NR^(c) R^(d), NR^(c) COR^(d), NR^(c)COOR^(d), COOR^(c) or CONR^(c) R^(d), where R^(c) and R^(d) are as abovedefined;

each R²³ represents C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, cyano,nitro, trifluoromethyl, trimethylsilyl, SR^(c), SOR^(c), SO₂ R^(c),OR^(c), NR^(c) R^(d), NR^(c) COR^(d), NR^(c) COOR^(d), COOR^(c) orCONR^(c) R^(d), where R^(c) and R^(d) are as above defined, preferablyhalo, such as chloro;

n is 0, 1, 2 or 3, preferably 0;

and salts and prodrugs thereof.

Particularly preferred are compounds of formula (Ia) wherein R²⁰ and R²¹are other than H and are located in the 3- and 5-positions. PreferablyR²⁰ and R²¹ each represent methyl or, more preferably, trifluoromethyl.

For use in medicine, the salts of the compounds of formula (I) will benon-toxic pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds according to the inventionor of their non-toxic pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds of this inventioninclude acid addition salts which may, for example, be formed by mixinga solution of the compound according to the invention with a solution ofa pharmaceutically acceptable non-toxic acid such as hydrochloric acid,oxalic acid, fumaric acid, p-toluenesulphonic acid, maleic acid,succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid orphosphoric acid. Salts of amine groups may also comprise quaternaryammonium salts in which the amino nitrogen atom carries a suitableorganic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety.Thus, for example, when both R¹ and R² are other than hydrogen, thenitrogen atom to which they are attached may be further substituted togive a quaternary ammonium salt. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include metal salts such as alkali metal salts, e.g.sodium or potassium salts; and alkaline earth metal salts, e.g. calciumor magnesium salts.

The present invention includes within its scope prodrugs of thecompounds of formula (I) above. In general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compound of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in "Design of Prodrugs",ed. H. Bundgaard, Elsevier, 1985.

The compounds according to the invention may exist both as enantiomersand as diastereomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention.

The invention also provides pharmaceutical compositions comprising oneor more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, sterile parenteral solutions or suspensions, or suppositories,for oral, parenteral or rectal administration. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a non-toxic pharmaceutically acceptable saltthereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective unit dosage forms such as tablets,pills and capsules. This solid preformulation composition is thensubdivided into unit dosage forms of the type described above containingfrom 0.1 to about 500 mg of the active ingredient of the presentinvention. The tablets or pills of the novel composition can be coatedor otherwise compounded to provide a dosage form affording the advantageof prolonged action. For example, the tablet or pill can comprise aninner dosage and an outer dosage component, the latter being in the formof an envelope over the former. The two components can be separated byan enteric layer which serves to resist disintegration in the stomachand permits the inner component to pass intact into the duodenum or tobe delayed in release. A variety of materials can be used for suchenteric layers or coatings, such materials including a number ofpolymeric acids and mixtures of polymeric acids with such materials asshellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone or gelatin.

The present invention futher provides a process for the preparation of apharmaceutical composition comprising a compound of formula (I), whichprocess comprises bringing a compound of formula (I) into associationwith a pharmaceutically acceptable carrier or excipient.

The compounds of formula (I) are of value in the treatment of a widevariety of clinical conditions which are characterised by the presenceof an excess of tachykinin, in particular substance P, activity. Thesemay include disorders of the central nervous system such as anxiety,depression, psychosis and schizophrenia; neurodegenerative disorderssuch as dementia, including senile dementia of the Alzheimer type,Alzheimer's disease and Down's syndrome; demyelinating diseases such asMS and ALS and other neuropathological disorders such as peripheralneuropathy, including diabetic and chemotherapy-induced neuropathy, andpostherpetic and other neuralgias; respiratory diseases such as chronicobstructive airways disease, bronchopneumonia, bronchospasm and asthma;inflammatory diseases such as inflammatory bowel disease, psoriasis,fibrositis, osteoarthritis and rheumatoid arthritis; allergies such aseczema and rhinitis; hypersensitivity disorders such as poison ivy;ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, andthe like; cutaneous diseases such as contact dermatitis, atropicdermatitis, urticaria, and other eczematoid dermatitis; addictiondisorders such as alcoholism; stress related somatic disorders; reflexsympathetic dystrophy such as shoulder/hand syndrome; dysthymicdisorders; adverse immunological reactions such as rejection oftransplanted tissues and disorders related to immune enhancement orsuppression such as systemic lupus erythematosis; gastrointestinal (GI)disorders and diseases of the GI tract such as disorders associated withthe neuronal control of viscera such as ulcerative colitis, Crohn'sdisease and incontinence; disorders of bladder function such as bladderdetrusor hyper-reflexia; fibrosing and collagen diseases such asscleroderma and eosinophilic fascioliasis; disorders of blood flowcaused by vasodilation and vasospastic diseases such as angina, migraineand Reynaud's disease; and pain or nociception, for example, thatattributable to or associated with any of the foregoing conditions,especially the transmission of pain in migraine. For example, thecompounds of formula (I) may suitably be used in the treatment ofdisorders of the central nervous system such as anxiety, psychosis andschizophrenia; neurodegenerative disorders such as senile dementia ofthe Alzheimer type, Alzheimer's disease and Down's syndrome; respiratorydiseases such as bronchospasm and asthma; inflammatory diseases such asinflammatory bowel disease, osteoarthritis and rheumatoid arthritis;adverse immunological reactions such as rejection of transplantedtissues; gastrointestinal (GI) disorders and diseases of the GI tractsuch as disorders associated with the neuronal control of viscera suchas ulcerative colitis, Crohn's disease and incontinence; disorders ofblood flow caused by vasodilation; and pain or nociception, for example,that attributable to or associated with any of the foregoing conditionsor the transmission of pain in migraine.

The compounds of formula (I) are particularly useful in the treatment ofpain or nociception and/or inflammation and disorders associatedtherewith such as, for example, neuropathy, such as diabetic andchemotherapy-induced neuropathy, postherpetic and other neuralgias,asthma, osteroarthritis, rheumatoid arthritis and especially migraine.

The present invention further provides a compound of formula (I), orN-(tert-butyoxycarbonyl)-D-4-hydroxyphenylglycine benzyl ester,1-acetamido-2-benzylthio-1-phenylethane,1-((cyanomethyl)amino)-2-benzyloxy-1-phenylethane orα-(acetyl-methylamino)-α-methyl-5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidineaceticacid, phenylmethylester, for use in therapy.

In the treatment of conditions involving actions of tachykinins releasedphysiologically in response to noxious or other stimuli, a suitabledosage level is about 0.001 to 50 mg/kg per day, preferably about 0.005to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day. Thecompounds may be administered on a regimen of 1 to 4 times per day,preferably once daily.

According to a further or alternative aspect, the present inventionprovides a method of treatment of a human or animal subject sufferingfrom or susceptible to a condition characterised by the presence of anexcess of tachykinin which method comprises administering to a human oranimal subject in need of such treatment an effective amount of acompound of formula (I), orN-(tert-butyoxycarbonyl)-D-4-hydroxyphenylglycine benzyl ester,1-acetamido-2-benzylthio-1-phenylethane,1-((cyanomethyl)amino)-2-benzyloxy-1-phenylethane orα-(acetyl-methylamino)-α-methyl-5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidineaceticacid, phenylmethylester or a salt or prodrug thereof.

The present invention also provides the use of a compound of formula(I), or N-(tert-butyoxycarbonyl)-D-4-hydroxyphenylglycine benzyl ester,1-acetamido-2-benzylthio-1-phenylethane,1-((cyanomethyl)amino)-2-benzyloxy-1-phenylethane orα-(acetyl-methylamino)-α-methyl-5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidineaceticacid, phenylmethylester, or a salt or prodrug thereof, for themanufacture of a medicament for the treatment of conditionscharacterised by the presence of an excess of tachykinins.

According to one general process (a) the compounds according to theinvention may be prepared by reaction of a compound of formula (II)##STR10## wherein Q, R¹, R², R³, X, Y and Z are defined as for formula(I), with a compound of formula HalCHR⁴ R⁵, where R⁴ and R⁵ are asdefined for formula (I) and Hal is halo, such as bromo, chloro or iodo,in the presence of a base.

The reaction is conveniently carried out in a suitable organic solvent,such as ether, for example, tetrahydrofuran.

Suitable bases of use in the reaction include alkali or alkaline earthmetal hydrides, for example, sodium hydride.

According to an alternative process, (b), compounds of formula (I)wherein R¹ and R³ are H may be prepared from intermediates of formula(IIIA) ##STR11## wherein Q, X, Y, Z, R⁴ and R⁵ are as defined forformula (I) and W represents NOH (IIIA) via a process which comprisesreduction.

Suitable reducing agents of use in the reduction include borane,catalytic hydrogenation in the presence of a suitable catalyst, such asa nobel metal catalyst, for example palladium, which may be supported,for example, on carbon, nickel, dissolving metal reduction, for exampleusing an alkali metal, such as sodium, in an alcohol, such as ethanol,or sodium amalgam.

A preferred reducing agent is borane. The borane reduction is preferablyeffected at elevated temperature, such as about 105°-110° C.

Compounds of formula (I) may also be prepared from other compounds offormula (I). Thus, for example, compounds of formula (I) wherein R¹represents H may be reacted with an optionally substituted alkylating oran acylating agent to produce compounds of formula (I) wherein R¹represent an optionally substituted alkyl or an acyl group. Suitableprocedures will be readily apparent to one skilled in the art.

Conversely, compounds of formula (I) wherein R¹ represents, for example,an acyl or a benzyl group, may be converted to compounds of formula (I)wherein R¹ represents H by, for example, hydrolysis or catalytichydrogenation. Suitable reagents and conditions are described in theaccompanying examples, or will be readily apparent to one skilled in theart of organic chemistry.

Compounds of formula (II) wherein Z is O and X and Y together representa group ═O are commercially available or may be prepared, for example,from intermediates of formula (IV) ##STR12## wherein Q and R³ are asabove defined and Ph represents phenyl, by hydrolysis.

The reaction is conveniently effected by heating a solution of thecompound of formula (IV) in concentrated hydrochloric acid at reflux.

Compounds of formula (II) wherein Z is O and X and Y are ═O may also beprepared by conventional procedures for the preparation of amino acidswhich are well documented and are described, for example, in Chemistryand Biochemistry of the Amino Acids, ed. G. C. Barrett, Chapman andHall, 1985.

Compounds of formula (II) wherein Z is S may be prepared from thecorresponding compounds of formula (II) wherein Z is O by treating thelatter compound with Lawesson's reagent or phosphorus pentasulphide in asuitable solvent, e.g. pyridine, at ambient or elevated temperature,suitably at the reflux temperature of the chosen solvent.

Compounds of formula (II) wherein X and Y represent H may be preparedfrom the corresponding compounds of formula (II) wherein X and Ytogether represent ═O, by reduction.

Suitable reducing agents include metal hydrides, such as lithiumaluminium hydride. The reaction is conveniently effected in a suitableorganic solvent, such as ether, for example, tetrahydrofuran, suitablyat elevated temperature, such as the reflux temperature of the solvent.

Intermediates of formula (IV) may be prepared from compounds of formula(V) ##STR13## wherein R³ is as defined for formula (I), by reaction witha compound of formula Q--Hal wherein Hal is halo, such as bromo, chloroor iodo, in the presence of a base.

Suitable bases of use in the reaction include metal hydroxides, forexample, sodium hydroxide. The reaction is conveniently effected in amixture of water and a suitable organic solvent, such as a hydrocarbon,for example, toluene, in the presence of a phase transfer catalyst, suchas benzyltrimethyl ammonium chloride.

Compounds of formula (V) are commercially available or may be preparedby procedures readily apparent to one skilled in the art.

Compounds of formula Q--Hal are commercially available or may beprepared by conventional procedures known to those skilled in the art.

Compounds of formula (IIIA) may be prepared from the correspondingcompounds of formula (III) wherein W represents O (IIIB) by reactionwith hydroxylamine or a suitable derivative thereof.

Conveniently the reaction will carried out in an aqueous organic solventsuch as, for example, aqueous methanol. Preferably the reaction mixturewill be buffered to approximately pH 4 by addition of a suitable salt,such as, for example sodium citrate.

Compounds of formula (IIIB) may be prepared by reaction of a compound offormula (VI) ##STR14## wherein X, Y, Z, R⁴ and R⁵ are as defined forformula (I) and R⁶⁰ represents an alkyl group, with a compound offormula Q--COHal, where Hal represents halo such as chloro or bromo andQ is as above defined, by the method described by J. W. Labadie et. al.,J. Org. Chem. Soc., 1983, 48, 4634.

Intermediates of formula (VI) may be prepared by analogous methods tothat described by W. C. Still, J. Am. Chem. Soc., 1978, 100, 1481.

Intermediates of formula (III) are novel compounds and form a furtheraspect of the present invention.

Where the above-described process for the preparation of the compoundsaccording to the invention gives rise to mixtures of stereoisomers theseisomers may, if desired, be separated, suitably by conventionaltechniques such as preparative chromatography.

The novel compounds may be prepared in racemic form, or individualenantiomers may be prepared either by enantiospecific synthesis or byresolution. The novel compounds may, for example, be resolved into theircomponent enantiomers by standard techniques, such as the formation ofdiastereomeric pairs by salt formation with an optically active acid,such as (-)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-1-tartaric acid followed by fractional crystallizationand regeneration of the free base. The novel compounds may also beresolved by formation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene and P. G. M. Wutts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The following Examples 1, 2, 3, 4, 5, 10 and 11 illustrate thepreparation of compounds according to the invention.

DESCRIPTION 11-(3,5-Dimethylphenyl)methyloxy)-(2S)-2-ammonium-2-phenylethane oxylatesalt

a) L-2-Phenylglycinol (5 g) and di-t-butyldicarbonate (9.4 g) wasstirred in a dichloromethane solution (30 ml) at room temperature for 3hours. The precipitate which formed was filtered to giveN-t-butoxycarbonyl-L-2-phenylglycinol, 4 g.

b) N-t-Butoxycarbonyl-L-2-phenylglycinol (2 g, part (a), was dissolvedin a mixture of dimethylformamide (2 ml) and tetrahydrofuran (10 ml).Sodium hydride (80%) was added to this over a 10 minute period withstirring under nitrogen at room temperature. After a further 15 min,3,5-dimethylbenzyl bromide was added and the reaction left to stir for 4hours. To the solution was added water (102 ml), and the productextracted into ethyl acetate. The organic phase was washed twice withwater and dried (MgSO₄). The solvent was removed in vacuo and theresidue chromatographed in a column containing silica gel eluting with100% petrol (bp 60°-70° C.) and 5% ethyl acetate/95% petrol (bp 60°-80°C.), to give1-(3,5-dimethylphenyl)methyloxy-(2S)-2-t-butoxycarbonylamino-2-phenylethane,0.9 g, mp 46°-49° C. ¹ H NMR (360MHz, CDCl₃) δ 7.38-7.22 (5H, m), 6.90(1H, s), 6.83 (2H, s), 5.28 (1H, bs), 4.84 (1H, bs), 4.46 (1H, d,Jgem=11.9Hz, OCH_(A) H_(B) Ph), 4.38 (1H, d, Jgem=11.9Hz, OCH_(A) H_(B)Ph), 3.69 (1H, dd, J=9.74Hz and 4.39Hz), 3.60 (1H, m), 2.28 (6H, s),1.40 (9H, s). m/z (CI⁺) 356 (M+H). Found: C, 74.37; H, 8.03; N, 3.97.C₂₂ H₂₉ NO₃ requires C, 74.33; H, 8.22; N, 3.94%.

c) 1-(3,5-Dimethylphenyl)methyloxy(2S)-2-t-butoxycarbonylamino-2-phenylethane (0.2 g; part (b)) wasdissolved in trifluoroacetic acid for 10 mins then evaporated todryness. To a solution of the residue dissolved in methanol was addedoxalic acid (70 mg). The solvent was removed in vacuo and the residuerecrystallized from diethylether/petrol (bp 60°-80° C.) to give the1-(3,5-dimethylphenyl)methyloxy-(2S)-2-ammonium-2-phenylethane oxalatesalt, 0.114 g, 135°-137° C. ¹ H NMR (360MHz, DMSO) δ 7.51-7.38 (5H, m),6.90 (3H, s), 4.52 (1H, dd, J=7.37Hz and 5.0Hz), 4.48 (2H, d, J=1.8Hz),3.76-3.66 (2H, m), 2.24 (6H, s). Found: C, 65.07; H, 6.61; N, 4.00. C₁₇H₂₁ NO.1.1C₂ H₂ O₄ requires C, 65.07; H, 6.60; N, 3.95%.

EXAMPLE 1L-1-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-(t-butoxycarbonylamino)-2-phenylethane

2-N-t-Butoxycarbonylamino-L-2-phenylglycinol (Description 1a, 1g) wasalkylated with 3,5-bis(trifluoromethyl)benzyl bromide in a manneranalogous to that described in Description 1b to give the titlecompound, mp 52°-53° C., m/e (CI⁺)=464 (M+H), (CI⁻)=462 (M-H). Found: C,56.99; H, 4.67; N, 3.05: C₂₂ H₂₂ F₆ NO₃ requires: C, 57.02; H, 5.00; N,3.02%.

DESCRIPTION 2L-2-Ammonium-1-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylethaneoxalate salt

L-1-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-t-butoxycarbonylamino-L-2-phenylglycinol(Example 1) was deprotected in an analogous manner to that described inDescription 1c to give the title compound, mp 84°-90° C. ¹ H NMR (MeOHd₄, 360MHz) δ 7.97 (2H, s), 7.89 (1H, s), 7.47-7.41 (5H, m), 4.8 (2H, ABJgem=12.7Hz), 4.61 (1H, t, J=5.93Hz), 3.9 (2H, d, J=5.27Hz). m/e(CI⁺)=364. Found: C, 48.46; H, 3.75; N, 2.94. C₁₇ H₁₅ F₆ NO.1.4(C₂ H₂O₄) requires C, 48.60; H, 3.67; N, 2.86%.

EXAMPLE 21-((3,5-Dimethylphenyl)methyloxy)-(2S)-2-(((Carbomethoxy)methyl)amino)-2-phenylethane

1-((3,5-Dimethylphenyl)methyloxy)-(2S)-2-t-butoxycarbonylamino-2-phenylethane(1.9 g, Description 1b) was treated with trifluoroacetic acid. After 10minutes the solvent was removed in vacuo and the residue partitionedbetween dichloromethane and 2M-NaOH. The organic phase was washed withwater, dried (MgSO₄) and evaporated in vacuo. To a solution of theresidue in tetrahydrofuran (20 ml) was added methyl bromoacetate (0.51ml) and triethylamine (0.56 g) and the solution heated to reflux for 16hours. Ethyl acetate and water were added and the organic phase washedwith water, saturated brine and dried (MgSO₄). The residue obtainedafter removal of the solvent in vacuo was chromatographed on silica geleluting with ethyl acetate/petroleum ether bp 60°-80° C. (1:1) to givethe title compound 1.6 g as an oil. Found: C, 73.13; H, 7.75; N, 4.32.C₂₀ H₂₅ NO₃ requires C, 73.37; H, 7.70; N, 4.28%.

EXAMPLE 3(2S)-2-(((Carboxamido)methyl)ammonium)-1-((3,5-dimethylphenyl)methyloxy)-2-phenylethaneoxalate salt

The product of Example 2 (0.8 g) was dissolved in methanol (20 ml)saturated with ammonia at 0° C. After the solution had been stored at+5° C. for 4 days in a sealed flask the solution was evaporated todryness and chromatographed on silica gel eluting with ethyl acetate. Asolution of the product and oxalic acid in methanol was evaporated todryness and the residue crystallised from hot diethyl ether to give thetitle compound, mp=86°-89° C. Found: C, 60.10; H, 6.35; N, 6.64. C₁₉ H₂₄N₂ O₂.(C₂ H₂ O₄)₁.3 requires C, 60.41; H, 6.24; N, 6.52%.

EXAMPLE 4(2S)-1-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-(((carbomethoxy)methyl)ammonium)-2-phenylethaneoxalate salt

The title compound was prepared from(2S)-2-amino-2-phenyl-1-((bis(trifluoromethyl)phenyl)methyloxy)-2-phenylethane(Description 2) using an analogous procedure to that described inExample 2, mp 95°-97° C. Found: C, 49.33; H, 3.82; N, 2.61. C₂₀ H₁₉ F₆NO₃.(C₂ H₂ O₄)₁.2 requires C, 49.51; H, 3.97; N, 2.58%.

EXAMPLE 5(2S)-1-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-(((carboxamido)methyl)ammonium)-2-phenylethaneoxalate salt

The title compound was prepared from the product of Example 4 using ananalogous procedure to that described in Example 3, mp: 147°-151° C.Found: C, 49.35; H, 4.07; N, 5.47. C₁₉ H₁₈ F₆ N₂ O₂.C₂ H₂ O₄ requires C,49.42; H, 3.95; N, 5.49%.

EXAMPLE 62-Ammonium-1-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-(4-chlorophenyl)ethaneoxalate salt monohydrate

a) Potassium hydroxide (27.0 g), lithium chloride (6.75 g) andtriethylbenzylammonium chloride (1.84 g) were dissolved indichloromethane (40 ml) and 33% aqueous ammonia solution (45 ml) andgaseous ammonia bubbled through this solution at 0° C. for 5 minutes. Asolution of p-chlorobenzaldehyde (11.2 g) and chloroform (10.2 ml) indichloromethane (40 ml) was added over 1 hour whilst maintaining thetemperature at 0° C. and this mixture stirred under a continuous streamof ammonia at 0° C. for 6 hours and at room temperature for a further 18hours. Water (120 ml) and dichloromethane (40 ml) were added, theaqueous layer was further extracted with dichloromethane, concentratedin vacuo, filtered and adjusted to pH 6-7 with concentrated hydrochloricacid. On cooling to 0° C. a precipitate formed and was collected byfiltration, washed with ethanol and water and dried to giveα-(4-chlorophenyl)glycine, 4.2 g.

b) The amino acid (part (a), 4.2 g) was added portionwise to a refluxingsuspension of lithium aluminium hydride (1.2 g) in tetrahydrofuran (72ml) and the mixture heated under reflux for a further 6 hours. Thesolution was cooled to room temperature and 10% sodium hydroxidesolution (1.92 ml) added dropwise followed by water (2.4 ml). A solutionof di-tert-butyl dicarbonate (7.0 g) and 4-dimethylaminopyridine (96 mg)in dichloromethane (38 ml) was added and the resulting mixture heatedunder reflux for 6 hours then cooled to room temperature and filteredthrough a pad of anhydrous sodium sulphate. The resulting crude mixturewas purified by chromatography on silica gel to give2-(N-t-butoxycarbonylamino)-2-(4-chlorophenyl)ethanol.

c) The product (part (b), 1.0 g) was alkylated with3,5-bis(trifluoromethyl)benzyl bromide followed by deprotection withtrifluoroacetic acid in an analogous manner to that described in Example2b and 2c respectively to give the title compound. Found: C, 45.19; H,3.27; N, 2.61. C₁₇ H₁₄ ClF₆ NO. C₂ H₂ O₄.H₂ O requires C, 45.12; H,3.59; N, 2.78%.

EXAMPLE 72-Ammonium-1-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-(3-chlorophenyl)ethaneoxalate salt

The title compound was prepared by a method analogous to that describedin Example 6 using m-chlorobenzaldehyde as starting material. Found: C,46.60; H, 3.37; N, 2.89. C₁₇ H₁₄ ClF₆ NO. C₂ H₂ O₄ requires: C, 46.28;H, 3.31; N, 2.87%.

EXAMPLE 82-Ammonium-1-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-(2-chlorophenyl)ethaneoxalate salt

a) Sodium hydride (80% suspension in oil, 2.03 g) was washed twice withpetroleum ether and to this solid was added tetrahydrofuran (50 ml) anddimethylformamide (3 ml) followed by the slow addition of a solution of3,5-bis(trifluoromethyl)benzyl alcohol (15 g) in tetrahydrofuran (50ml). After the effervescence had subsided (30 minutes) a solution oftri-n-butyltinmethylene iodide (25.2 g) was added. The solution washeated to reflux for 2 hours, cooled to room temperature and quenched bycareful addition of petroleum ether bp 60°-80° C. (500 ml) and water(200 ml). The organic phase was washed with water and dried (MgSO₄).After removal of the solvent in vacuo the residue was distilled underreduced pressure bp ₀.8 =140° C. to givetri-n-butyl-((3,5-bis(trifluoromethyl)phenyl) methyloxymethyl)tin. ¹ HNMR (360MHz, CDCl₃) δ 7.78 (1H, s, aryl 4CH), 7.76 (2H, s, aryl 2,6-CH),4.52 (2H, s, aryl-CH₂).

b) 2-Chlorobenzoyl chloride (1.27 ml),tri-n-butyl-((3,5-bis(trifluoromethyl)phenyl)methyloxymethyl)tin (part(a), 6.2 g) and benzylchlorobis(triphenylphosphine)palladium (II) (80mg) were dissolved in chloroform (10 ml) and the solution heated to 70°C. for 36 hours. On cooling diethyl ether and saturated aqueouspotassium fluoride were added and this solution filtered through a padof Hyflo. The organic layer was washed with water, dried (MgSO₄) andreduced in vacuo giving a residue which was purified by chromatographyon silica gel to give 2'-chloro-2-((3,5-bis(trifluoromethyl)phenyl)methyloxy)acetophenone, ¹ H NMR (360MHz, CDCl₃) δ 7.79 (3H, bs, bis(CF₃)aryl CH2,4,6), 7.54-7.26 (4H, m, aryl), 4.75 (2H, s), 4.76 (2H, s).

c) The product of part (b) (1.05 g), sodium acetate (1.06 g) andhydroxylmine hydrochloride were dissolved in methanol (20 ml) and thesolution stirred for 24 hours. Water was added and the mixture extractedwith diethyl ether. The organic layer was washed with water, dried(MgSO₄) and reduced in vacuo to give2'-chloro-2-((3,5-bis(trifluoromethyl) phenyl)methyloxy)acetophenoneoxime.

d) A solution of borane (10 ml, 1M in tetrahydrofuran) was added to asolution of the product of part (c) in tetrahydrofuran and the mixtureheated under reflux for 48 hours. 5N hydrochloric acid was added andrefluxing continued for 2 hours. On cooling diethyl ether was added andthe solution washed with 2N aqueous sodium hydroxide. The organic layerwas dried (MgSO₄) and reduced in vacuo to give a residue which wasdissolved in methanol and treated with hydrogen gas at 50 psi over a 10%palladium on carbon catalyst for 2 hours. This mixture was filtered,reduced in vacuo and the residue partitioned between 5N hydrochloricacid and diethyl ether. The ether phase was washed with aqueouspotassium hydroxide and dried (MgSO₄). Oxalic acid (150 mg) was addedand the solution allowed to stand for 24 hours when the title compoundwas collected as a precipitate (200 mg). Found: C, 46.81; H, 3.63; N,2.64%; C₁₇ H₁₄ ClF₆ NO(COOH)₂ requires: C, 46.28; H, 3.31; N, 2.87%.

EXAMPLE 91-Ammonium-2-((bis(trifluoromethyl)phenyl)methyloxy)-1-phenylpropaneoxalate salt hemihydrate

a) To a cooled (-30° C.) solution of N-t-butoxycarbonyl(α-phenyl)glycine (40 g) and triethylamine (110 ml) in dimethyformamide(500 ml) was added iso-butylchloroformate (34.4 ml) at such a rate thatthe temperature of the solution remained below -20° C. After stirringfor 15 minutes to the solution was added N,O-dimethylhydroxylaminehydrochloride (52 g) and CH₂ Cl₂ (800 ml). The solution was stirred atroom temperature for 16 hours. Ethyl acetate was added and the solutionwas washed with 10% aqueous citric acid solution, water (3 times),saturated NaHCO₃ solution and dried (MgSO₄). The solvent was removed invacuo and the resultant solid washed with hexane to giveN'-t-butoxycarbonyl (α-phenyl)glycine N,O-dimethylhydroxamate, 37 g.

b) To a cooled (0° C.) solution of the product of part (a) (1.0 g) intetrahydrofuran (10 ml) was slowly added methyl magnesium bromide (6.8ml). After stirring the solution at room temperature for 2 hours 10%aqueous citric acid and ethyl acetate were added and the organic phasewashed further with water (2 times) and dried (MgSO₄). The solvent wasremoved in vacuo and to a solution of the residue in ethanol was addedsodium borohydride (0.13 g) for 2 hours. The solvent was removed invacuo and a solution of the residue in CH₂ Cl₂ was washed with water (3times) and dried (MgSO₄) to give upon evaporation in vacuo1-N-t-butoxycarbonylamino-1-phenylpropan-2-ol as a mixture ofdiastereomers.

c) The product of part (b) was alkylated with3,5-bis(trifluoromethyl)benzyl bromide in a manner analogous to thatdescribed in Description 1b to give2-((bis(trifluoromethyl)phenyl)methyloxy)-1-(N-t-butoxycarbonylamino)-1-phenylpropaneas a mixture (approx 3:1) of diastereomers. This material (0.56 g) wasdissolved in trifluoroacetic acid (20 ml) for 10 minutes followed byevaporation in vacuo. A solution of the residue in CH₂ Cl₂ was washedwith 2N-NaOH, water (2 times), saturated brine and dried (MgSO₄). Afterremoval of the solvent in vacuo the residue was crystallized by additionof oxalic acid (0.84 g) followed by recrystallization from diethylether/petroleum ether to give the title compound, mp 60°-62° C. Found:C, 50.17; H, 4.20; N, 2.84. C₁₈ H₁₇ F₆ NO. C₂ H₂ O₄.0.5(H₂ O) requires:C, 50.43; H, 4.23; N, 2.94%.

EXAMPLE 10L-1-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-((Cyanomethyl)amino)-2-phenylethane

A solution ofL-2-Amino-1-(3,5-bis(trifluoromethyl)phenyl)methyloxy-2-phenylethane(1.5 g, Description 2, free base), bromoacetonitrile (0.5 g) andtriethylamine (0.4 g) in tetrahydrofuran (10 ml) was heated under refluxfor 6 hours. After cooling to room temperature and evaporation in vacuo,a solution of the residue in ethyl acetate was washed with water (3times), saturated brine and dried (MgSO₄). The solvent was removed invacuo and the residue purified by silica gel chromatography (elutingwith 20-30% ethyl acetate in petroleum ether bp 60°-80° C.) to give thetitle compound as a crystalline solid. Found: C, 56.91; H, 4.21; N,6.97. C₁₉ H₁₅ F₆ N₂ O requires: C, 56.72; H, 4.01; N, 6.96%.

EXAMPLE 11 L-1-((Bis(trifluoromethyl)phenyl)methyloxy)-2-N-formamido-2-phenylethane

L-2-Amino-1-((bis(trifluoromethyl)phenyl)methyloxy)-2-phenylethane(Description 2, free base, 1.2 g) was treated with formic aceticanhydride (prepared by heating acetic anhydride 0.5 g and formic acid0.19 ml at 80° C. for 15 minutes) for 16 hours at room temperature. Thesolution was evaporated to dryness to give an oil which crystallized onstanding. This solid was recrystallized from ethyl acetate/petroleumether to give a mixture (approx 6:1) ofL-1-((bis(trifluoromethyl)phenyl)methyloxy)-2-N-formamido-2-phenylethaneandL-1-((bis(trifluoromethyl)phenyl)methyloxy)-2-N-acetarnido-2-phenylethanemp 96°-99° C. Found: C, 55.50; H, 4.07; N, 3.49: C₁₈ H₁₅ NO₂ F₆ requiresC, 55.25; H, 3.86; N, 3.58%. m/e (CI⁺) 392 (M+H), (CI⁻)=390 (M-H).

The following examples illustrate pharmaceutical compositions accordingto the invention.

EXAMPLE 12A

Tablets Containing 1-25 mg of Compound

    ______________________________________                                                       Amount mg                                                      ______________________________________                                        Compound of formula (I)                                                                        1.0       2.0    25.0                                        Microcrystalline cellulose                                                                     20.0      20.0   20.0                                        Modified food corn starch                                                                      20.0      20.0   20.0                                        Lactose          58.5      57.5   34.5                                        Magnesium Stearate                                                                             0.5       0.5    0.5                                         ______________________________________                                    

EXAMPLE 12B

Tablets Containing 26-100 mg of Compound

    ______________________________________                                                       Amount mg                                                      ______________________________________                                        Compound of formula (I)                                                                        26.0      50.0   100.0                                       Microcrystalline cellulose                                                                     80.0      80.0   80.0                                        Modified food corn starch                                                                      80.0      80.0   80.0                                        Lactose          213.5     189.5  139.5                                       Magnesium Stearate                                                                             0.5       0.5    0.5                                         ______________________________________                                    

The compound of formula (I), cellulose, lactose and a portion of thecorn starch are mixed and granulated with 10% corn starch paste. Theresulting granulation is sieved, dried and blended with the remainder ofthe corn starch and the magnesium stearate. The resulting granulation isthen compressed into tablets containing 1.0 mg, 2.0 mg, 25.0 mg, 26.0mg, 50.0 mg and 100 mg of the active compound per tablet.

EXAMPLE 13

Parenteral Injection

    ______________________________________                                                            Amount mg                                                 ______________________________________                                        Compound of formula (I)                                                                             1 to 100 mg                                             Citric Acid Monohydrate                                                                             0.75     mg                                             Sodium Phosphate      4.5      mg                                             Sodium Chloride       9        mg                                             Water for injection   to 1     ml                                             ______________________________________                                    

The sodium phosphate, citric acid monohydrate and sodium chloride aredissolved in a portion of the water. The compound of formula (I) isdissolved or suspended in the solution and made up to volume.

EXAMPLE 14

Topical Formulation

    ______________________________________                                                             Amount mg                                                ______________________________________                                        Compound of formula (I)                                                                              1-10    g                                              Emulsifying Wax        30      g                                              Liquid paraffin        20      g                                              White Soft Paraffin    to 100  g                                              ______________________________________                                    

The white soft paraffin is heated until molten. The liquid paraffin andemulsifying wax are incorporated and stirred until dissolved. Thecompound of formula (I) is added and stirring continued until dispersed.The mixture is then cooled until solid.

SUBSTANCE P ANTAGONISM ASSAY A. Receptor Expression in Monkey KidneyCell Line (COS)

To express the cloned human neurokinin-1-receptor (NK1R) transiently inCOS, the cDNA for the human NK1R was cloned into the expression vectorpCDM9 which was derived from pCDM8 (INVITROGEN) by inserting theampicillin resistance gene (nucleotide 1973 to 2964 from BLUESCRIPT SK+(trademark, STRATAGENE, La Jolla, Calif., USA)) into the Sac II site.Transfection of 20 ug of the plasmid DNA into 10 million COS cells wasachieved by electroporation in 800 μl of transfection buffer (135 mMNaCl, 1.2 mM CaCl₂, 1.2 mM MgCl₂, 2.4 mM K₂ HPO₄, 0.6 mM KH₂ PO₄, 10 mMglucose, 10 mM N-2-hydroxyethyl-piperazine-N'-2-ethane sulphonic acid(HEPES) pH 7.4) at 260 V and 950 μF using the IBI GENEZAPPER (trademarkIBI, New Haven, Conn., USA). The cells were incubated in 10% fetal calfserum, 2 mM glutamine, 100 U/ml penicillin-streptomycin, and 90% DMEMmedia (GIBCO, Grand Island, N.Y., USA) in 5% CO₂ at 37° C. for threedays before the binding assay.

B. Stable Expression in Chinese Hamster Ovarian Cell Line

To establish a stable cell line expressing cloned human NK1R, the cDNAwas subcloned into the vector pRcCMV (INVITROGEN). Transfection of 20 ugof the plasmid DNA into CHO cells was achieved by electroporation in 800μl of transfection buffer supplemented with 0.625 mg/ml Herring spermDNA at 300 V and 950 μF using the IBI GENEZAPPER (IBI). The transfectedcells were incubated in CHO media [10% fetal calf serum, 100 U/mlpenicillin-streptomycin, 2 mM glutamine, 1/500 hypoxanthinethymidine(ATCC), 90% IMDM media (JRH BIOSCIENCES, Lenexa, Kans., USA), 0.7 mg/mlG418 (GIBCO)] in 5% CO₂ at 37° C. until colonies were visible. Eachcolony was separated and propagated. The cell clone with the highestnumber of human NK1R was selected for subsequent applications such asdrug screening.

C. Assay Protocol using COS or CHO

The binding assay of human NK1R expressed in either COS or CHO cells isbased on the use of ¹²⁵ I-substance P (¹²⁵ I-SP, from DU PONT, Boston,Mass.) as a radioactively labeled ligand which competes with unlabeledsubstance P or any other ligand for binding to the human NK1R. Monolayercell cultures of COS or CHO were dissociated by the non-enzymaticsolution (SPECIALTY MEDIA, Lavellette, N.J.) and resuspended inappropriate volume of the binding buffer (50 mM Tris pH 7.5, 5 mM MnCl₂,150 mM NaCl, 0.04 mg/ml bacitracin, 0.004 mg/ml leupeptin, 0.2 mg/mlBSA, 0.01 mM phosphoramidon) such that 200 μl of the cell suspensionwould give rise to about 10,000 cpm of specific ¹²⁵ I-SP binding(approximately 50,000 to 200,000 cells). In the binding assay, 200 ul ofcells were added to a tube containing 20 ul of 1.5 to 2.5 nM of ¹²⁵ I-SPand 20 μl of unlabeled substance P or any other test compound. The tubeswere incubated at 4° C. or at room temperature for 1 hour with gentleshaking. The bound radioactivity was separated from unboundradioactivity by GF/C filter (BRANDEL, Gaithersburg, Md.) which waspre-wetted with 0.1% polyethylenimine. The filter was washed with 3 mlof wash buffer (50 mM Tris pH 7.5, 5 mM MnCl₂, 150 mM NaCl) three timesand its radioactivity was determined by gamma counter.

The activation of phospholiphase C by NK1R may also be measured in CHOcells expressing the human NK1R by determining the accumulation ofinositol monophosphate which is a degradation product of IP₃. CHO cellsare seeded in 12-well plate at 250,000 cells per well. After incubatingin CHO media for 4 days, cells are loaded with 5μCi of ³ H-myoinositolin 1 ml of media per well by overnight incubation. The extracellularradioactivity is removed by washing with phosphate buffered saline. LiClis added to the well at final concentration of 10 mM with or without thetest compound, and incubation is continued at 37° C. for 15 min.Substance P is added to the well at final concentration of 0.3 nM toactivate the human NK1R. After 30 min of incubation at 37° C., themedium is removed and 0.1N HCl is added. Each well is sonicated at 4° C.and extracted with CHCl₃ /methanol (1:1). The aqueous phase is appliedto a 1 ml Dowex AG 1×8 ion exchange column. The column is washed with0.1N formic acid followed by 0.025M ammonium formate-0.1N formic acid.The inositol monophosphate is eluted with 0.2M ammonium formate-0.1Nformic acid and quantitated by beta counter.

The data in Table 1 were obtained for compounds of formula (I):

                  TABLE 1                                                         ______________________________________                                        SUBSTANCE P ANTAGONISM RESULTS                                                Compound of Ex #                                                                              IC.sub.50 @ NK1R (nM)                                         ______________________________________                                        1               400                                                           2               140                                                           3               100                                                           4                45                                                           5                6                                                            10               15                                                           11               60                                                           ______________________________________                                    

    __________________________________________________________________________    SEQUENCE LISTING                                                              (1) GENERAL INFORMATION:                                                      (iii) NUMBER OF SEQUENCES: 3                                                  (2) INFORMATION FOR SEQ ID NO:1:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 11 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (iii) HYPOTHETICAL: NO                                                        (iv) ANTI-SENSE: NO                                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:                                       ArgProLysProGlnGlnPhePheGlyLeuMet                                             1510                                                                          (2) INFORMATION FOR SEQ ID NO:2:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (iii) HYPOTHETICAL: NO                                                        (iv) ANTI-SENSE: NO                                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:                                       HisLysThrAspSerPheValGlyLeuMet                                                1510                                                                          (2) INFORMATION FOR SEQ ID NO:3:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (iii) HYPOTHETICAL: NO                                                        (iv) ANTI-SENSE: NO                                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:                                       AspMetHisAspPhePheValGlyLeuMet                                                1510                                                                          __________________________________________________________________________

We claim:
 1. A method for the treatment of pain, inflammation, migraineor postherpetic neuralgia, which method comprises administration to apatient in need thereof of a tachykinin-reducing amount of a compound offormula (I), or a pharmaceutically acceptable salt thereof: ##STR15##wherein Q represents optionally substituted phenyl or optionallysubstituted naphthyl;X and Y each represent H, C₁₋₆ alkyl, C₂₋₆ alkenylor X and Y together form a group ═O; Z represents O or S; R¹ representsH; C₁₋₆ alkyl optionally substituted by hydroxy, cyano, COR^(a),COOR^(a), CONR^(a) R^(b), COC₁₋₄ alkylNR^(a) R^(b), CONR^(a) C₁₋₄alkylCONR^(a) R^(b) or NR^(a) R^(b), (where R^(a) and R^(b) eachindependently represent H, C₁₋₆ alkyl, phenyl optionally substituted byone or two of C₁₋₆ alkyl, C₁₋₆ alkoxy, halo or trifluoromethyl orphenyl(C₁₋₄ alkyl) optionally substituted in the phenyl ring by one ortwo of C₁₋₆ alkyl, C₁₋₆ alkoxy, halo or trifluoromethyl); phenyl(C₁₋₄alkyl) (optionally substituted in the phenyl ring by one or two of C₁₋₆alkyl, C₁₋₆ alkoxy, halo or trifluoromethyl); C₂₋₆ alkenyl; COR^(a) ;COOR^(a) ; CONHR^(a) ; COC₁₋₆ alkylhalo; COC₁₋₆ alkylNR^(a) R^(b) ; orCONR^(a) C₁₋₆ alkylCONR^(a) R^(b), where R^(a) and R^(b) are aspreviously defined; R² represents C₁₋₆ alkyl substituted by hydroxy,cyano, COR^(a), COOR^(a), CONR^(a) R^(b), COC₁₋₄ alkylNR^(a) R^(b),CONR^(a) C₁₋₄ alkylCONR^(a) R^(b) or NR^(a) R^(b), (where R^(a) andR^(b) are as above defined); phenyl(C₁₋₄ alkyl) (optionally substitutedby one or two of C₁₋₆ alkyl, C₁₋₆ alkoxy, halo and trifluoromethyl inthe phenyl ring); C₂₋₆ alkenyl; COR^(a) ; COOR^(a) ; CONHR^(a) ; COC₁₋₆alkylhalo; COC₁₋₆ alkylNR^(a) R^(b) ; or CONR^(a) C₁₋₆ alkylCONR^(a)R^(b), where R^(a) and R^(b) are as previously defined; R³ represents Hor C₁₋₆ alkyl; R⁴ represents H, C₁₋₆ alkyl or phenyl (optionallysubstituted by one or two of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,halo, cyano, nitro, trifluoromethyl, trimethylsilyl, SR^(c), SOR^(c),SO₂ R^(c), OR^(c), NR^(c) R^(d), NR^(c) COR^(d), NR^(c) COOR^(d),COOR^(c) or CONR^(c) R^(d), where R^(c) and R^(d) each independentlyrepresent H, C₁₋₆ alkyl, phenyl or trifluoromethyl); and R⁵ represents(CH₂)_(q) phenyl, wherein q is 0, 1, 2 or 3, which may optionally besubstituted in the phenyl ring by one or two of C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, halo, cyano, nitro, trifluoromethyl,trimethylsilyl, SR^(c), SOR^(c), SO₂ R^(c), OR^(c), NR^(c) R^(d), NR^(c)COR^(d), NR^(c) COOR^(d), COOR^(c) or CONR^(c) R^(d), where R^(c) andR^(d) are as above defined.
 2. A method as claimed in claim 1 wherein R¹represents H; C₁₋₆ alkyl optionally substituted by hydroxy, cyano,COR^(a), COOR^(a), CONR^(a) R^(b), COC₁₋₄ alkylNR^(a) R^(b), CONR^(a)C₁₋₄ alkylCONR^(a) R^(b) or NR^(a) R^(b), (where R^(a) and R^(b) eachare as previously defined); phenyl(C₁₋₄ alkyl) (optionally substitutedin the phenyl ring by one or two of C₁₋₆ alkyl, C₁₋₆ alkoxy, halo andtrifluoromethyl); C₂₋₆ alkenyl; COR^(a) ; COOR^(a) ; CONHR^(a) ; COC₁₋₄alkylNR^(a) R^(b) ; or CONR^(a) C₁₋₄ alkylCONR^(a) R^(b) (where R^(a)and R^(b) are as previously defined) and R² represents C₁₋₆ alkylsubstituted by hydroxy, cyano, COR^(a), COOR^(a), CONR^(a) R^(b), COC₁₋₄alkylNR^(a) R^(b), CONR^(a) C₁₋₄ alkylCONR^(a) R^(b) or NR^(a) R^(b),(where R^(a) and R^(b) each are as previously defined); phenyl(C₁₋₄alkyl) (optionally substituted in the phenyl ring by one or two of C₁₋₆alkyl, C₁₋₆ alkoxy, halo and trifluoromethyl); C₂₋₆ alkenyl; COR^(a) ;COOR^(a) ; CONHR^(a) ; COC₁₋₄ alkylNR^(a) R^(b) ; or CONR^(a) C₁₋₄alkylCONR^(a) R^(b) (where R^(a) and R^(b) are as previously defined).3. A method as claimed in claim 1 wherein R¹ represents H, C₁₋₆ alkyl,phenyl(C₁₋₄ alkyl), COR^(a), COOR^(a) or CONHR^(a), where R^(a) is C₁₋₆alkyl or phenyl, and R² represents phenyl(C₁₋₄ alkyl), COR^(a), COOR^(a)or CONHR^(a), where R^(a) is C₁₋₆ alkyl or phenyl.
 4. A method asclaimed in claim 1 wherein R¹ is H or methyl and R² is C₁₋₂ alkylsubstituted by a group selected from hydroxy, cyano, CHO, CO₂ (C₁₋₆alkyl), CONR^(a) R^(b) and NR^(a) R^(b).
 5. A method as claimed in claim1 wherein Q is unsubstituted or substituted phenyl; R⁴ is H; and R⁵ issubstituted phenyl.
 6. A method as claimed in claim 1 wherein X and Yboth represent H and Z represents O.
 7. A method as claimed in claim 1wherein the compound of formula (I) is selectedfrom:L-1-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-(t-butoxycarbonylamino)-2-phenylethane;1-((3,5-dimethylphenyl)methyloxy)-2(S)-2-(((carbomethoxy)methyl)amino)-2-phenylethane;(2S)-1-(((carboxamido)methyl)ammonium)-1-((3,5-dimethylphenyl)methyloxy)-2-phenylethane;(2S)-1-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-(((carbomethoxy)methyl)ammonium)-2-phenylethane;(2S)-2-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-(((carboxamido)methyl)ammonium)-2-phenylethane;L-1-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-((cyanomethyl)amino)-2-phenylethane;L-1-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-N-formamido-2-phenylethane;ora pharmaceutically acceptable salt thereof.
 8. A compound of formula(I'), or a pharmaceutically acceptable salt thereof: ##STR16## whereinQ' represents unsubstituted or substituted phenyl;X and Y each representH, C₁₋₆ alkyl, C₂₋₆ alkenyl or X and Y together form a group ═O; Zrepresents O or S; R¹ represents H; C₁₋₆ alkyl optionally substituted byhydroxy, cyano, COR^(a), COOR^(a), CONR^(a) R^(b), COC₁₋₄ alkylNR^(a)R^(b), CONR^(a) C₁₋₄ alkylCONR^(a) R^(b) or NR^(a) R^(b), (where R^(a)and R^(b) each independently represent H, C₁₋₆ alkyl, phenyl optionallysubstituted by one or two of C₁₋₆ alkyl, C₁₋₆ alkoxy, halo ortrifluoromethyl or phenyl(C₁₋₄ alkyl) optionally substituted in thephenyl ring by one or two of C₁₋₆ alkyl, C₁₋₆ alkoxy, halo ortrifluoromethyl); phenyl(C₁₋₄ alkyl) (optionally substituted in thephenyl ring by one or two of C₁₋₆ alkyl, C₁₋₆ alkoxy, halo ortrifluoromethyl); C₂₋₆ alkenyl; COR^(a) ; COOR^(a) ; CONHR^(a) ; COC₁₋₆alkylhalo; COC₁₋₆ alkylNR^(a) R^(b) ; or CONR^(a) C₁₋₆ alkylCONR^(a)R^(b), where R^(a) and R^(b) are as previously defined; R² representsC₁₋₆ alkyl substituted by hydroxy, cyano, COR^(a), COOR^(a), CONR^(a)R^(b), COC₁₋₄ alkylNR^(a) R^(b), CONR^(a) C₁₋₄ alkylCONR^(a) R^(b) orNR^(a) R^(b), (where R^(a) and R^(b) are as above defined); phenyl(C₁₋₄alkyl) (optionally substituted by one or two of C₁₋₆ alkyl, C₁₋₆ alkoxy,halo and trifluoromethyl in the phenyl ring); C₂₋₆ alkenyl; COR^(a) ;COOR^(a) ; CONHR^(a) ; COC₁₋₆ alkylhalo; COC₁₋₆ alkylNR^(a) R^(b) ; orCONR^(a) C₁₋₆ alkylCONR^(a) R^(b), where R^(a) and R^(b) are aspreviously defined; R³ represents H or C₁₋₆ alkyl; and R⁵ representsphenyl substituted by one or two groups selected from methoxy, nitro,cyano, halo and trifluoromethyl.
 9. A compound selectedfrom:L-1-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-(t-butoxycarbonylamino)-2-phenylethane;1-((3,5-dimethylphenyl)methyloxy)-2(S)-2-(((carbomethoxy)methyl)amino)-2-phenylethane;(2S)-1-(((carboxamido)methyl)ammonium)-1-((3,5-dimethylphenyl)methyloxy)-2-phenylethane;(2S)-1-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-(((carbomethoxy)methyl)ammonium)-2-phenylethane;(2S)-2-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-(((carboxamido)methyl)ammonium)-2-phenylethane;L-1-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-((cyanomethyl)amino)-2-phenylethane;L-1-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-N-formamido-2-phenylethane;ora pharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundas claimed in claim 8 in association with a pharmaceutically acceptablecarrier.
 11. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound as claimed in claim 9 in association witha pharmaceutically acceptable carrier.